Although irreversible reactions of glycolysis represent major regulatory steps in gluconeogenesis, common reversible reactions between the two opposite pathways may also serve as regulatory and committed steps of these pathways under certain circumstances. Our present results showing a substantial decrease in PGK-1
Z-FA-FMK in the mutant regenerated liver seem to be the case, since intermediate metabolites such as 3-PG and PEP, downstream metabolites of PGK-1 reaction in glycolysis, were accumulated to greater extents in mutant regenerated liver than in the control one. Such down-regulation of PGK-1 is likely to occur at transcriptional level given that PH-elicited induction of PGK-1 mRNA was significantly suppressed in the mutant liver. This notion is further supported by a previous report showing that a conserved HIF-1-binding site in the promoter region of PGK-1 is prerequisite for hypoxic induction of the gene via HIF-1 [13]. On the other hand, expressions of other HIF-1-inducible glycolytic
enzymes including GAPDH and GK did not change by PH and were comparable between control and HIFKO mice, revealing complicated HIF-1-dependent and -independent regulations of enzyme expressions in the liver. Collectively, these results provide another HIF-1-dependent regulatory mechanism for the maintenance of enhanced gluconeogenic flux during liver regeneration by up-regulating PGK-1 expression.
